Testosterone treatment: who will benefit the most?
Authors: Linghui Deng, Qiu Shi
Journal: The Lancet Healthy Longevity (2023)

As a natural aspect of the ageing process in men, testosterone production can decrease, leading to a condition called low testosterone. This decline can result in various physical health challenges, including sexual dysfunction, reduced libido, fatigue, and muscle weakness.1Snyder PJ Bhasin S Cunningham GR et al.Effects of testosterone treatment in older men.N Engl J Med. 2016; 374: 611-624Crossref PubMed Scopus (577) Google Scholar Although conditions such as Klinefelter syndrome and hypopituitarism can cause low testosterone at a young age (by age 30 years or younger), the majority of testosterone prescriptions are issued to older inviduals with low testosterone due to factors such as obesity or diabetes.2Jayasena CN Anderson RA Llahana S et al.Society for Endocrinology guidelines for testosterone replacement therapy in male hypogonadism.Clin Endocrinol (Oxf). 2022; 96: 200-219Crossref PubMed Scopus (0) Google Scholar Efforts to assess the effectiveness of testosterone replacement therapy to treat low testosterone in older men (aged 65 years and older) have sparked persistent debate and controversy. Studies offer mixed results; whereas some indicate benefits such as increased muscle mass, improved mood, and enhanced sexual function, others highlight the potential risks, such as cardiovascular and prostate health issues.3Lincoff AM Bhasin S Flevaris P et al.Cardiovascular safety of testosterone-replacement therapy.N Engl J Med. 2023; 389: 107-117Crossref PubMed Scopus (7) Google Scholar The ideal candidates for positive responses to testosterone treatment remain unclear, and this uncertainty leads to a lack of clear guidelines and conflicting evidence, creating considerable challenges for clinical practice, policy decisions, and future research. A meta-analysis, guided by established protocols, provides a robust method to draw more generalisable conclusions than do individual studies. In The Lancet Healthy Longevity, Jemma Hudson and colleagues4Hudson J Cruickshank M Quinton R et al.Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis.Lancet Healthy Longev. 2023; 4: e561-e572Google Scholar report findings from a meta-analysis of both individual participant data and aggregate data, which was conducted to identify which patient subgroups would most benefit from testosterone treatment. The study was conducted with the Testosterone Efficacy and Safety (TestES) Consortium,5National Institute for Health and Care ResearchTestosterone effects and safety in men with low testosterone levels (TESTES): an evidence synthesis and economic evaluation.https://www.fundingawards.nihr.ac.uk/award/17/68/01Date: 2018Date accessed: September 5, 2022Google Scholar ensuring good data quality control and facilitating subgroup analyses. In an analysis of more than 3000 men from 17 randomised clinical trials providing individual participant data, Hudson and colleagues found a generally low risk of bias in the trials. Patient age, BMI, and diabetes status did not significantly affect the short-to-medium-term effectiveness of testosterone treatment in improving erectile dysfunction or quality of life. However, older individuals and those with obesity appeared to have a smaller improvement in sexual function, potentially due to more severe baseline symptoms. The authors observed that testosterone treatment alone might effectively address mild erectile dysfunction in men with non-classic low testosterone (with a minimal clinically important difference in 15-item International Index of Erectile Function score of 2·13). However, for men with moderate or severe erectile dysfunction, who require minimal clinically important differences of 5 and 7, respectively, to perceive clinically meaningful changes, the impact of testosterone might be less substantial. Of note, unlike phosphodiesterase inhibitors, testosterone also enhances other aspects of sexual function, such as sexual desire. Consequently, the benefits of testosterone for sexual function might be underestimated if only its effect on erectile dysfunction improvement is considered. The one-stage and two-stage meta-analyses conducted by Hudson and colleagues offer a crucial contribution to the research on this topic.4Hudson J Cruickshank M Quinton R et al.Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis.Lancet Healthy Longev. 2023; 4: e561-e572Google Scholar Their approach involves extracting individual participant data from each study, as opposed to relying solely on summarised statistics, such as means and SDs. This method typically yields more precise effect estimates and provides a deeper insight into heterogeneity. Furthermore, it enhances the authors’ control over data quality and consistency throughout the analysis. Given the study's central aim of understanding the effect of testosterone in specific patient populations, the authors conducted detailed subgroup analyses and a thorough threshold analysis; they examined treatment effects within specific subpopulations, encompassing diverse age groups, individuals with obesity, and varying disease severity levels. Conducting such a granular analysis might not be possible with aggregated data alone.6Riley RD Debray TPA Fisher D et al.Individual participant data meta-analysis to examine interactions between treatment effect and participant-level covariates: statistical recommendations for conduct and planning.Stat Med. 2020; 39: 2115-2137Crossref PubMed Scopus (62) Google Scholar Several important considerations arise when interpreting the study's findings. Individual participant data were obtained from only about half of the eligible participants in the published trials. This limited dataset might explain the study's focus on men with serum total testosterone concentrations of less than 12 nmol/L, a high representation of White participants, and a predominance of non-smokers. Although no significant outcome disparities were detected between studies with and without individual participant data, potential selection bias in individual participant data meta-analysis when excluding specific studies or datasets must be acknowledged. Moreover, given recent progress in combining therapies for age-related conditions, evaluating the independent and combined benefits of other medications and lifestyle interventions alongside testosterone treatment in men with various health issues is crucial.7Zeng B Qiu S Xiong X et al.The effect of different administrations of testosterone therapy on adverse prostate events: a Bayesian network meta-analysis.Front Endocrinol (Lausanne). 2022; 131009900Crossref Scopus (0) Google Scholar Advanced analytical techniques, such as network meta-analyses or umbrella analyses, could facilitate this comprehensive assessment.8Zhang C Bian H Chen Z et al.The association between dietary inflammatory index and sex hormones among men in the United States.J Urol. 2021; 206: 97-103Crossref Scopus (23) Google Scholar In conclusion, the study by Hudson and colleagues shows that testosterone enhances sexual function in both younger and older men, although the relative benefit experienced by older men could be lower due to more severe symptoms before treatment. These findings can help health-care professionals and patients to better gauge the short-to-medium-term effectiveness of testosterone replacement therapy. We declare no competing interests. Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysisIn men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-medium-term testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity. Full-Text PDF Open Access